Monoclonal antibody therapy is an important component of the anti-cancer armamentarium, based on the specificity and versatility of antibodies. The anti-tumor effects of monoclonal antibodies are derived from two main mechanisms of action: modulating signal transduction and survival within, and inducing immune responses against tumor cells. Certain monoclonal antibodies can engage immune effectors- primarily natural killer (NK) cells-through Fc receptor-mediated interactions that induce antibody- dependent cellular cytotoxicity (ADCC). Preclinical and clinical evidence suggests that ADCC is important for anti-tumor responses for many therapeutic monoclonal antibodies. However, like most cancer therapeutics, tumors develop resistance to monoclonal antibody therapies. Genetic resistance determinants have been identified in oncogenic signaling networks-e.g., in the EGFR signaling network- whose modulation can enhance therapeutic response-e.g., EGFR-targeted small molecules or monoclonal antibodies-based on decrease in proliferation and enhanced cell death. However, it is plausible that resistance determinants could modulate tumor response to ADCC as well. Such determinants have not been identified. This project aims to elucidate novel tumor-based molecular determinants of ADCC that will enhance understanding and efficacy of monoclonal antibody therapy. The specific aims focus on assessing two putative mechanisms of resistance: oncogenic signaling networks that may promote escape from the cytotoxic effects of ADCC; and tumor-based modulation of immune synapse formation to evade ADCC. High-throughput functional genomics screening is used to assess genes whose knockdown modulates ADCC. Validation studies will be used to confirm screening results, followed by in vitro studies to identify specific mechanisms of ADCC modulation. Animal model studies will verify those molecular determinants whose modulation affects ADCC in vivo. The overall process is focused on discovering mechanisms of modulation of ADCC that enhance efficacy of monoclonal antibody therapies for the targeted treatment of human malignancies.